tbuckley/cabot-search huggingface dataset:
Survival outcomes used to generate version 9 American Joint Committee on Cancer staging system for anal cancer
Authors: Lauren M. Janczewski, Joseph Faski, Heidi Nelson, Marc J. Gollub, Cathy Eng, James D. Brierley, Joel M. Palefsky, Richard M. Goldberg, M. Kay Washington, Elliot A. Asare, Karyn A. Goodman
Journal: CA A Cancer Journal for Clinicians (2023)

Abstract The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including anal cancer, is the standard for cancer staging in the United States. The AJCC staging criteria are dynamic, and periodic updates are conducted to optimize AJCC staging definitions through a panel of experts charged with evaluating new evidence to implement changes. With greater availability of large data sets, the AJCC has since restructured and updated its processes, incorporating prospectively collected data to validate stage group revisions in the version 9 AJCC staging system, including anal cancer. Survival analysis using AJCC eighth edition staging guidelines revealed a lack of hierarchical order in which stage IIIA anal cancer was associated with a better prognosis than stage IIB disease, suggesting that, for anal cancer, tumor (T) category has a greater effect on survival than lymph node (N) category. Accordingly, version 9 stage groups have been appropriately adjusted to reflect contemporary long‐term outcomes. This article highlights the changes to the now published AJCC staging system for anal cancer, which: (1) redefined stage IIB as T1–T2N1M0 disease, (2) redefined stage IIIA as T3N0–N1M0 disease, and (3) eliminated stage 0 disease from its guidelines altogether.
Bleeding and Thrombotic Complications in Patients With Cirrhosis: A State-of-the-Art Appraisal
Authors: Pierre-Emmanuel Rautou, Stephen H. Caldwell, Erica Villa
Journal: Clinical Gastroenterology and Hepatology (2023)

Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non-portal hypertensive-related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration.
Iron deficiency in heart failure: screening, prevalence, incidence and outcome data from the <scp>Swedish</scp> Heart Failure Registry and the <scp>Stockholm CREAtinine</scp> Measurements collaborative project
Authors: Felix Lindberg, Lars H. Lund, Lina Benson, Cecilia Linde, Nicola Orsini, Juan Jesus Carrero, Gianluigi Savarese
Journal: European Journal of Heart Failure (2023)

Aims Iron deficiency (ID) is common in heart failure (HF) and linked with poor prognosis regardless of anaemia. We assessed temporal trends in ID testing, ID prevalence, ID incidence, iron need, and outcomes associated with ID in HF across the ejection fraction (EF) spectrum. Methods and results From the Swedish HF registry, we enrolled 15 197 patients from Region Stockholm with available EF and collected laboratory tests from routine practice. Iron screening improved since 2016 but remained &lt;25% as of 2018. In 1486 patients with iron biomarkers at baseline, the prevalence of ID was 55% (HF with reduced EF 54%; mildly reduced EF 51%; preserved EF 61%). Iron need was ≥1500 mg in 72% of patients. ID was independently associated with higher risk for HF rehospitalizations (incidence rate ratio [IRR] 1.62, 95% confidence interval [CI] 1.13–2.31) and with cardiovascular (CV) death or repeated HF hospitalizations (IRR 1.63, 95% CI 1.15–2.30) regardless of EF ( p ‐interaction 0.21 and 0.26, respectively), but not with all‐cause death, CV death, or first HF hospitalization. Among 96 patients without ID at baseline and with follow‐up iron biomarkers, 21% developed ID within 6 months. Conclusions Iron deficiency screening improved over time but is still limitedly implemented, despite being highly prevalent and incident, and independently associated with CV death or HF rehospitalizations regardless of EF. Most patients with ID had an iron need necessitating either repeated administrations of intravenous iron or a preparation permitting &gt;1000 mg doses. These data highlight the need for improved screening for ID in HF.
Hyponatraemia and changes in natraemia during hospitalization for acute heart failure and associations with in‐hospital and long‐term outcomes – from the<scp>ESC‐HFA EORP</scp>Heart Failure Long‐Term Registry
Authors: Agnieszka Kapłon‐Cieślicka, Lina Benson, Ovidiu Chioncel, Maria G. Crespo‐Leiro, Andrew J.S. Coats, Stefan D. Anker, Frank Ruschitzka, Camilla Hage, Jarosław Drożdż, Petar Seferovic, Giuseppe M.C. Rosano, Massimo Piepoli, Alexandre Mebazaa, Theresa McDonagh, Mitja Lainscak, Gianluigi Savarese, Roberto Ferrari, Wilfried Mullens, Antoni Bayes‐Genis, Aldo P. Maggioni, Lars H. Lund
Journal: European Journal of Heart Failure (2023)

To comprehensively assess hyponatraemia in acute heart failure (AHF) regarding prevalence, associations, hospital course, and post-discharge outcomes.Of 8298 patients in the European Society of Cardiology Heart Failure Long-Term Registry hospitalized for AHF with any ejection fraction, 20% presented with hyponatraemia (serum sodium <135 mmol/L). Independent predictors included lower systolic blood pressure, estimated glomerular filtration rate (eGFR) and haemoglobin, along with diabetes, hepatic disease, use of thiazide diuretics, mineralocorticoid receptor antagonists, digoxin, higher doses of loop diuretics, and non-use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers. In-hospital death occurred in 3.3%. The prevalence of hyponatraemia and in-hospital mortality with different combinations were: 9% hyponatraemia both at admission and discharge (hyponatraemia Yes/Yes, in-hospital mortality 6.9%), 11% Yes/No (in-hospital mortality 4.9%), 8% No/Yes (in-hospital mortality 4.7%), and 72% No/No (in-hospital mortality 2.4%). Correction of hyponatraemia was associated with improvement in eGFR. In-hospital development of hyponatraemia was associated with greater diuretic use and worsening eGFR but also more effective decongestion. Among hospital survivors, 12-month mortality was 19% and adjusted hazard ratios (95% confidence intervals) were for hyponatraemia Yes/Yes 1.60 (1.35-1.89), Yes/No 1.35 (1.14-1.59), and No/Yes 1.18 (0.96-1.45). For death or heart failure hospitalization they were 1.38 (1.21-1.58), 1.17 (1.02-1.33), and 1.09 (0.93-1.27), respectively.Among patients with AHF, 20% had hyponatraemia at admission, which was associated with more advanced heart failure and normalized in half of patients during hospitalization. Admission hyponatraemia (possibly dilutional), especially if it did not resolve, was associated with worse in-hospital and post-discharge outcomes. Hyponatraemia developing during hospitalization (possibly depletional) was associated with lower risk.
Table of Contents
Authors: M Lipsyc-Sharf, S Tolaney, A Falanga, C Ay, M Nisio, G Gerotziafas, L Jara-Palomares, F Langer, R Lecumberri, M Mandala, A Maraveyas, I Pabinger, M Sinn, K Syrigos, A Young, J Remon, B Besse, S Ponce, A Callejo, K Al-Rabi, R Bernabe, L Greillier, M Majem, N Reguart, I Monnet, S Cousin, P Garrido, G Robinet, R Campelo, A Madroszyk, J Mazières, H Curcio, B Wasąg, Y Pretzenbacher, B Fournier, A.-M Dingemans, R Dziadziuszko
Journal: Annals of Oncology (2023)
How Emergency Department Use in Ontario Can Help Determine the Right Dose of Telehealth
Authors: Jesse M. Pines
Journal: JAMA Network Open (2023)

Tara Kiran, MD, MSc; Michael E. Green, MD, MPH; Rachel Strauss, MPH; C. Fangyun Wu, MSc, MA; Maryam Daneshvarfard, MScCH; Alexander Kopp, BA; Lauren Lapointe-Shaw, MD, PhD; Lidija Latifovic, MSc; Eliot Frymire, MA, BEd; Richard H. Glazier, MD, MPH
The PHERCC Matrix. An Ethical Framework for Planning, Governing, and Evaluating Risk and Crisis Communication in the Context of Public Health Emergencies
Authors: Giovanni Spitale, Federico Germani, Nikola Biller-Andorno
Journal: The American Journal of Bioethics (2023)

Risk and crisis communication (RCC) is a current ethical issue subject to controversy, mainly due to the tension between individual liberty (a core component of fairness) and effectiveness. In this paper we propose a consistent definition of the RCC process in public health emergencies (PHERCC), which comprises six key elements: evidence, initiator, channel, publics, message, and feedback. Based on these elements and on a detailed analysis of their role in PHERCC, we present an ethical framework to help design, govern and evaluate PHERCC strategies. The framework aims to facilitate RCC, incorporating effectiveness, autonomy, and fairness. It comprises five operational ethical principles: openness, transparency, inclusivity, understandability, and privacy. The resulting matrix helps understanding the interplay between the PHERCC process and the principles of the framework. The paper includes suggestions and recommendations for the implementation of the PHERCC matrix.
Statins Are Associated With a Decreased Risk of Severe Liver Disease in Individuals With Noncirrhotic Chronic Liver Disease
Authors: Rajani Sharma, Tracey G. Simon, Hannes Hagström, Paul Lochhead, Bjorn Roelstraete, Jonas Söderling, Elizabeth C. Verna, Jean Emond, Jonas F. Ludvigsson
Journal: Clinical Gastroenterology and Hepatology (2023)
Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure
Authors: Veera Ganesh Yerra, Sri Nagarjun Batchu, Harmandeep Kaur, MD Golam Kabir, Youan Liu, Suzanne L. Advani, Duc Tin Tran, Shadi Sadeghian, Phelopater Sedrak, Filio Billia, Uros Kuzmanov, Anthony O. Gramolini, Deema O. Qasrawi, Evgeniy V. Petrotchenko, Christoph H. Borchers, Kim A. Connelly, Andrew Advani
Journal: Journal of Clinical Investigation (2023)

Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how inflammatory cells affect cardiomyocytes in the remodeling heart. Pathogenic cardiac macrophages induced an IFN response in cardiomyocytes, characterized by upregulation of the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), which posttranslationally modifies its targets through a process termed ISGylation. Cardiac ISG15 is controlled by type I IFN signaling, and ISG15 or ISGylation is upregulated in mice with transverse aortic constriction or infused with angiotensin II; rats with uninephrectomy and DOCA-salt, or pulmonary artery banding; cardiomyocytes exposed to IFNs or CD4+ T cell-conditioned medium; and ventricular tissue of humans with nonischemic cardiomyopathy. By nanoscale liquid chromatography-tandem mass spectrometry, we identified the myofibrillar protein filamin-C as an ISGylation target. ISG15 deficiency preserved cardiac function in mice with transverse aortic constriction and led to improved recovery of mouse hearts ex vivo. Metabolomics revealed that ISG15 regulates cardiac amino acid metabolism, whereas ISG15 deficiency prevented misfolded filamin-C accumulation and induced cardiomyocyte autophagy. In sum, ISG15 upregulation is a feature of pathological ventricular remodeling, and protein ISGylation is an inflammation-induced posttranslational modification that may contribute to heart failure development by altering cardiomyocyte protein turnover.
Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma
Authors: Mingen Lin, Jing He, Xinchao Zhang, Xue Sun, Wenjing Dong, Ruonan Zhang, Yanping Xu, Lei Lv
Journal: Journal of Clinical Investigation (2023)

How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.
NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression
Authors: Yen-Po Tsao, Fang-Yu Tseng, Chih-Wei Chao, Ming-Han Chen, Yi-Chen Yeh, Babamale Olarewaju Abdulkareem, Se-Yi Chen, Wen-Ting Chuang, Pei-Ching Chang, I-Chun Chen, Pin-Hsuan Wang, Chien-Sheng Wu, Chang-Youh Tsai, Szu-Ting Chen
Journal: Journal of Clinical Investigation (2023)
Re: Agrón et al.: Reticular pseudodrusen status, ARMS2/HTRA1 genotype, and geographic atrophy enlargement: Age-Related Eye Disease Study 2 Report 32. (Ophthalmology. 2022;129:1107–1119)
Authors: Alauddin Bhuiyan, Eric Souied, Rando L. Allikmets, R. Theodore Smith
Journal: Ophthalmology (2023)

Agron et al1 suggest that reticular pseudodrusen (or subretinal drusenoid deposits [SDDs]) and variant(s) in the ARMS2 locus are statistically independent risk factors for geographic atrophy (GA) enlargement. We believe these data can contribute to our understanding of the risks, lesions, and pathways to advanced age-related macular degeneration (AMD), of which GA enlargement is a part.
A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models
Authors: Jing Li, Xiangdong Zhu, Matt T Oberdier, Chunpei Lee, Shaoxia Lin, Sarah J Fink, Cody N Justice, Kevin Qin, Andrew W Begeman, Frederick C Damen, Hajwa Kim, Jiwang Chen, Kejia Cai, Henry R Halperin, Terry L Vanden Hoek
Journal: Journal of Clinical Investigation (2023)

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.
The transcriptional and regulatory identity of erythropoietin producing cells
Authors: Bjørt K. Kragesteen, Amir Giladi, Eyal David, Shahar Halevi, Laufey Geirsdóttir, Olga M. Lempke, Baoguo Li, Andreas M. Bapst, Ken Xie, Yonatan Katzenelenbogen, Sophie L. Dahl, Fadi Sheban, Anna Gurevich-Shapiro, Mor Zada, Truong San Phan, Roberto Avellino, Shuang-Yin Wang, Oren Barboy, Shir Shlomi-Loubaton, Sandra Winning, Philipp P. Markwerth, Snir Dekalo, Hadas Keren-Shaul, Merav Kedmi, Martin Sikora, Joachim Fandrey, Thorfinn S. Korneliussen, Josef T. Prchal, Barak Rosenzweig, Vladimir Yutkin, Fernando Racimo, Eske Willerslev, Chamutal Gur, Roland H. Wenger, Ido Amit
Journal: Nature Medicine (2023)
Aspirin and immunotherapy: a Faustian bargain?
Authors: Eric A Goethe, Amy B Heimberger, Ganesh Rao
Journal: Journal of Clinical Investigation (2023)

Fibrinogen-like protein 1 (FGL1) has been associated with improved survival in hepatocellular carcinoma (HCC). However, recent evidence suggests that FGL1 may bind to surface receptors on lymphocytes and induce immune senescence. In this issue of the JCI, Lin and co-authors show that FGL1 may be acetylated by aspirin and targeted for degradation, which is associated with increased antitumor immunity and improved survival. Similar findings were obtained with inhibitors of sirtuin 2 (SIRT2), a histone deacetylase. These findings expand our current understanding of the role of FGL1 in cancer and provide an impetus for the evaluation of alternative immunotherapy combinations in HCC.
Targeting immune cell trafficking and vascular endothelial cells in psoriasis
Authors: Kelly Z Young, Olesya Plazyo, Johann E Gudjonsson
Journal: Journal of Clinical Investigation (2023)

The role of the vasculature in inflammatory skin disorders is an exciting area of investigation. Vascular endothelial cells (ECs) play instrumental roles in maintaining the vascular barrier and control of blood flow. Furthermore, ECs contribute to a variety of immune responses, such as targeting immune cells to specific areas of vascular damage, infection, or foreign material. However, mechanisms through which ECs participate in immune-mediated responses remain to be fully explored. In this issue of the JCI, Li, Shao, et al. report on vascular endothelial glycocalyx destruction and the mechanisms through which EC dysfunction contributes to the well-characterized immune-mediated features of psoriasis, a chronic inflammatory skin disease. Here, we discuss the implications of these findings and highlight some risks and benefits of existing therapies designed to target immune cell trafficking in a variety of inflammatory conditions.
Renal proximal tubule cells: power and finesse
Authors: Michaela Aa Fuchs, Myles Wolf
Journal: Journal of Clinical Investigation (2023)

The proximal tubule is the high-capacity reabsorptive powerhouse of the kidney. Two papers in recent issues of the JCI highlight mechanisms of more delicate effects of the proximal tubule. Yoon et al. demonstrated the intracellular mechanism by which parathyroid hormone (PTH) increases production of 1,25-vitamin D. Activation of PTH receptor 1/cAMP/PKA signaling inhibited salt-inducible kinase 2 (SIK2) and SIK3, which increased CYB27B1 transcription and 1,25-vitamin D production. Replication of these effects with small-molecule SIK inhibitors suggests possible therapeutic applications for patients with disorders characterized by 1,25-vitamin D deficiency. Zhou et al. discovered that proximal tubule glycolysis acts as a phosphate sensor that regulates fibroblast growth factor 23 production in bone. They described several kidney-specific metabolic modifications that enabled glycolysis to be deployed as a phosphate sensor. The provocative results raise intriguing questions with implications for patients with disorders of phosphate homeostasis, including chronic kidney disease.
iPSC–derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function
Authors: Kevin T Eade, Brendan Robert E Ansell, Sarah Giles, Regis Fallon, Sarah Harkins-Perry, Takayuki Nagasaki, Simone Tzaridis, Martina Wallace, Elizabeth A Mills, Samaneh Farashi, Alec Johnson, Lydia Sauer, Barbara Hart, M Elena Diaz-Rubio, Melanie Bahlo, Christian Metallo, Rando Allikmets, Marin L Gantner, Paul S Bernstein, Martin Friedlander
Journal: Journal of Clinical Investigation (2023)

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease-contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway.
CPR: cardiac phosphatase in resuscitation
Authors: Arjun Deb
Journal: Journal of Clinical Investigation (2023)

Out-of-hospital cardiac arrest is associated with a dismal mortality rate and low long-term survival. A large pharmacological knowledge gap exists in identifying drugs that preserve neurological function and increase long-term survival after cardiac arrest. In this issue of the JCI, Li, Zhu, and colleagues report on their engineering of a 20-amino acid cell-permeable peptide (TAT-PHLPP9c) that antagonized the phosphatase PHLPP1 and prevented PHLPP1-mediated dephosphorylation and AKT inactivation. TAT-PHLPP9c administration maintained activated AKT after arrest and led to AKT-mediated beneficial effects on the heart, brain, and metabolism, resulting in increased cardiac output and cerebral blood flow and rescue of ATP levels in affected tissues. TAT-PHLPP9c improved neurological outcomes and increased survival after cardiac arrest in murine and porcine models of cardiac arrest. These findings provide proof of concept that pharmacological targeting of PHLPP1 may be a promising approach to augmenting long-term survival after cardiac arrest.